Mechanical apparatus and method for dilating and delivering a therapeutic agent to a site of treatment

ABSTRACT

A mechanical dilatation and medicament delivery device for enlarging a flow passage of a vessel by dilating and delivering a liposome or micelle-encapsulated therapeutic agent or medicament to an obstruction in the vessel. The present invention comprises a substantially cylindrically shaped expansion member and includes a means engaged to the expansion member for altering the distance between the proximal end and the distal end of the expansion member thereby transforming the expansion member between a diametrically contracted configuration to diametrically expanded configuration. A liposome or micelle-encapsulated therapeutic agent or medicament is coated on either the expansion member, or incorporated into a substrate coated on the expansion member. The present method comprises the steps of advancing the coated expansion member to the obstruction in a vessel and applying opposed forces on said expansion member in an axial direction to move the expansion member to an expanded configuration wherein the expansion member dilates the obstruction and the expansion member either passively or actively delivers a liposome or micelle-encapsulated therapeutic agent or medicament to the obstruction.

PRIOR APPLICATIONS

This application is a divisional of application Ser. No. 10/135,709filed on Apr. 30, 2002.

BACKGROUND OF THE INVENTION

Cardiovascular disease is commonly accepted as being one of the mostserious health risks facing our society today. Diseased and obstructedcoronary arteries can restrict the flow of blood and cause tissueischemia and necrosis. While the exact etiology of scleroticcardiovascular disease is still in question, the treatment of narrowedcoronary arteries is more defined. Surgical construction of coronaryartery bypass grafts (CABG) is often the method of choice when there areseveral diseased segments in one or multiple arteries. Open heartsurgery is, of course, very traumatic for patients. In many cases, lesstraumatic, alternative methods are available for treating cardiovasculardisease percutaneously. These alternate treatment methods generallyemploy various types of percutaneous transluminal angioplasty (PTCA)balloons or excising devices (atherectomy) to remodel or debulk diseasedvessel segments. A further alternative treatment method involvespercutaneous, intraluminal installation of expandable, tubular stents orprostheses in sclerotic lesions.

A recurrent problem with the previous devices and PTCA procedures istheir failure to maintain patency due to the growth of injured vasculartissue. This is known as “restenosis” and may be a result of theoriginal injury to the vessel wall occurring during the angioplastyprocedure. Pathologically restenosis represents a neointimalproliferative response characterized by smooth muscle cell hyperplasiathat results in reblockage of the vessel lumen necessitating repeat PTCAprocedures up to 35-50% of all cases. It has been generally acceptedthat a certain therapeutic agents or medicaments may be capable ofselectively inhibiting the growth of these hyperproliferating smoothmuscle cells and thereby reduce the rate of restenosis after the primaryinterventional procedure.

Heretofore, various devices have been disclosed which may be used todeliver a therapeutic agent or medicament to a blood vessel whileundergoing angioplasty. Balloon angioplasty catheters have been used toplace and deliver a various therapeutic agents or medicaments withinhuman vessels. For example, in U.S. Pat. Nos. 5,112,305, 5,746,716,5,681,281, 5,873,852, 5,713,863 and 6,102,904 disclose and claim aballoon catheter system with various injector plates mounted on theballoon for delivering a drug into an arterial segment.

Alternatively a standard angioplasty balloon may be coated with apolymeric material which is then used to bond certain medicaments ortheraputic agents. These agents are then delivered to the desiredtherapeutic site by inflation of the balloon and diffusion of themedicatment or therpeutic agent into the vessel wall. Only limitedquantities of therapeutic agents can be delivered because of “wash-out”of the drug into the circulation during balloon placement and due to thelimited time the inflated balloon can be left in place due to ischemiacaused by the balloon.

In addition, previously disclosed methods of delivering drug to a siteof treatment are described which utilize iontophoretic orelectrophoretic means as disclosed in U.S. Pat. No. 5,499,971. Usingthese iontophoretic or electroporetic means passive diffusion of thedrug or medicament is enhanced by placing the medicament or theraputicagent in close proximity to the site of treatment and then usingelectrically to augment delivery of the drug into the tissues or cells.These methods generally place the drug inside a balloon mounted distallyon a catheter whereby the balloon is composed of a semi-porous materialthrough which the drug can diffuse.

Alternatively the electrodes themselves may be used as a method foriontophoretic or electroporetic drug delivery. One such method isdisclosed in U.S. Pat. No. 6,219,577 which describes coating the surfaceof band-like electrodes with a polymer which bonds the drug and deliversit to the site of treatment. This method has the disadvantage of nothave the capability to dilate the obstruction prior or concurrent to thedelivery of a drug. Additionally the surface area of contact of theelectrode bands with the vessel wall are limited to only the centralportion of the arc shaped bands. This limits the contact surface area ofthe drug coated electrodes. This method also has the inherentdisadvantage that since the site of therapy is intravascular, most ofthe drug will be washed off or dissolved off the electrodes into thecirculating blood stream before it is advanced through the vascularsystem from its percutaneous entry and to the distal site of treatment.This again limits the amount of the drug delivered to the site and alsopotentially subjects the patient to harmful or toxic systemic exposure.

Additional devices have been disclosed which attempt to improve thedepth of penetration into tissue by pressure driving a solution of thedrug into the vessel wall through small orifices in the balloonmaterial. There is, however, some evidence that high pressure “jetting”of a drug solution out of small pores close to the vessel lumen can infact cause vessel wall injury. The development of double skinned,microporous (or weeping) balloons obviated this “jetting” effect to someextent, but diffusion of the drug into the vessel wall is still slow,and much of the drug can be lost through subsequent “washout effects”.This method leads to limited amounts of drugs or therapeutics agentsdelivered to the tissues or cells. Furthermore, in all of these methodsthe balloon must be expanded and thereby restricts blood flow to thedistal arterial segments while the balloon is in the expandedconfiguration thus limiting the time the drug delivering balloon can beclinically utilized.

There are also several disadvantages using either a stent or ballooncatheter to delivery a therapeutic agent or medicament to a vascularsegment. Regarding the therapeutic agent eluting stents, once the stentis deployed, there is no means outside of invasive surgical excision, toremove the eluting stent from the vascular segment. Therefore, stents orimplanted prostheses with therapeutic agent eluting properties must beprecisely calibrated to deliver an exact quantity of the therapeuticagent or medicament to the vascular segment upon stent deployment.Balloon catheters employed to delivery a therapeutic agent or medicamentto a vascular segment have limitations including potential balloonrupture and ischemia due to balloon inflation limiting distal blood flowto the artery. This leads to tissue ischemia and potential necrosis.Even “perfusion” type angioplasty balloons used to delivery atherapeutic agent or medicament to the affected artery provide far lessthan physiological blood flow during balloon inflation and dwell timesare limited by ischemia and tissue necrosis.

Recent studies have demonstrated the effectiveness of a number of agents(e.g., paclitaxel, rapamycin, Actinomycin D) on the prevention ofunwanted cellular proliferation. These agents have proven efficacy inthe treatment of cancer and transplant rejection. A major advantage ofthese agents is the high lipid solubility that causes tissue levels tobe high for an extended period of time since they cannot be rapidlycleared. However, this advantage is also a disadvantage because thedelivery of these medicaments must generally pass hydrophilicboundaries.

Thus, it can be seen that there is a need for a new and improved deviceto selectively delivery a therapeutic agent or medicament to an arterialsegment and which overcomes these disadvantages.

In general, it is an object of this present invention to provide amechanical dilatation device and method which is capable of dilating anobstruction within a vascular segment while delivering, either passivelyor by an electrically active means, a therapeutic agent or medicament tothe vessel segment.

Another object of the invention is to provide a method to deliver highconcentrations of agents that are poorly soluble or insoluble in aqueousmedia to selected sites in the body including arteries, veins or othertubular structures, prosthetic devices such as grafts, and tissues suchas, but not limited to, brain, myocardium, colon, liver, breast andlung.

Another object of the invention is to provide a percutaneous device andmethod of the above character which can be used for prolonged periods inexposing or delivering a therapeutic agent or medicament to a vascularsegment while allowing continuous perfusion of blood into the vesseldistal to the treatment area.

Another object of the invention is to provide a device that can controlthe release or diffusion of a medicament or therapeutic agent tominimize potential systemic affects and maximize the diffusion ordelivery of the medicament or therapeutic agent to the site oftreatment.

Another object of the invention is to provide a device that is notsusceptible to structural damage (balloon rupture) and subsequentrelease of therapeutic agents or drug materials into the vasculature.

SUMMARY OF THE INVENTION

It is known that therapeutic agent therapy can reduce the proliferationof rapidly growing cells. The present invention employs various means ofdelivery with a mechanical dilatation device for enlarging a flowpassage of a vessel by dilating and delivering a liposome or micelle ormicelle-encapsulated therapeutic agent or medicament to an obstructionin a vessel. Since the therapeutic agent or medicament is capable ofselectively inhibiting the growth of proliferating cells, the presentinvention not only achieves acute patency of a vessel but employsmedical therapy to maintain chronic patency through the prevention ofrestenosis.

The present invention comprises a substantially cylindrically shapedexpansion member and includes a means engaged to the expansion memberfor altering the distance between the proximal end and the distal end ofthe expansion member thereby transforming the expansion member between adiametrically contracted configuration and a diametrically expandedconfiguration. A liposome or micelle-encapsulated therapeutic agent ormedicament can be coated directly on the expansion member oralternatively, the therapeutic agent or medicament can be incorporatedinto a polymer or other substrate coated on the expansion mesh. Ifdesired, the same or another therapeutic agent or medicament can becoated on the marker bands mounted on the catheter located within theexpansion mesh or injected through a delivery lumen which has a distalport located inside the expansion member. Due to its unique design, thepresent invention has significant perfusion capability which allows thecatheter and its distal expansion member or mesh to be in a expandedconfiguration and engaged to the vessel wall for proloned periods. Thisallows sufficient time for passive or electrically active migration ofthe therapeutic agent or medicament to the vessel or organ withoutcausing ischemic related events. The catheter also comprises either anover-the-wire or rapid exchange designs.

The present invention also can include a conduction means that provideselectrical communication from a connector on the proximal end of thecatheter to the distal conductive flexible elongate elements therebyproviding the distal expandable mesh with a means to control orfacilitate the release or delivery of a medicament or therapeutic agentto a treatment site. In this embodiment, the invention relates tocatheter-based devices which provide an electrical driving force thatcan increase the rate of migration of liposome or micelle-encapsulatedmedicaments and other therapeutic agents from the expansion member andinto body tissues and cells using iontophoresis only, electroporationonly, or combined iontophoresis and electroporation. In addition, acharge can be applied to the expansion member that is opposite theliposome or micelle-encapsulated therapeutic agent or medicament, or tothe substrate that incorporates the therapeutic agent or medicament inorder to create a significant bond between the therapeutic agent and theexpandable mesh.

The invention also takes advantage of the prior body of knowledge thathas demonstrated the enhanced solubility and delivery of agents afterthey have been incorporated into liposome and micelles. Since liposomeor micelles and micelles possess both lipophilic and hydrophilicregions, they can be used to solubilize compounds that are insoluble inwater. If charged liposome or micelles are used, these charged moleculescan move in an electrical field.

This disclosure demonstrates the delivery of uncharged, lipophilicmedicaments or agents by incorporating them into charged liposome ormicelles and then delivering them to the target site by electrophoresis.

The present method also comprises the steps of advancing the catheterand expansion member to the obstruction in a vessel and applying opposedforces on said expansion member in an axial direction to move theexpansion member to an expanded configuration wherein the expansionmember dilates the obstruction and the catheter/expansion memberassembly actively (or passively) delivers the liposome ormicelle-encapsulated therapeutic agent or medicament to the obstruction.

One preferable approach may be to 1) energize the catheter to create abond between the therapeutic agent and expansion mesh and then advancethe system to the treatment segment, 2) expand the expansion member todilate the segment, 3) allow perfusion to passively transfer thetherapeutic agent into the tissues.

Another preferable approach may be to 1) energize the catheter to createa bond between the liposome or micelle enclosed therapeutic agent andexpansion mesh and then advance the system to the treatment segment, 2)expand the expansion member to dilate the segment while allowingperfusion, 3) apply electrical energy to cause iontophoresis of thetherapeutic agent into the tissues and/or 4) apply electrical energy forelectroporation to be applied to permeabilize the cells. Preferably, thecatheter is able to perform steps 2, 3 and 4 sequentially withoutrepositioning of the catheter. Even more preferably, the catheter isdesigned to maintain a high concentration of drug in the tissueextracellular spaces (e.g. by iontophoresis) such that the subsequentcreation of transient pores in cell surface membranes by electroporationpulses results in greatly improved intracellular delivery of themedicament or therapeutic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side-elevational view partially in section of a mechanicaldilatation and medicament delivery device incorporating the presentinvention.

FIG. 2 is a cross-sectional view taken along the line 2-2 of FIG. 1.

FIG. 3 is a cross-sectional view taken along the line 3-3 of FIG. 1.

FIG. 4 is a cross-sectional view taken along the line 4-4 of FIG. 1.

FIG. 5 is a cross-sectional view taken along the line 5-5 of FIG. 1.

FIG. 6 is a cross-sectional view taken along the line 6-6 of FIG. 1.

FIG. 7 is a greatly enlarged view of a portion of the dilatation andmedicament delivery device in a partially expanded state.

FIGS. 8 a-8 f depict a variety of electric waveforms for use iniontophoresis and electrophoresis with the catheter and distal mesh ofthe present invention.

FIG. 9 is a partial side-elevational view of another embodiment of amechanical dilatation and medicament delivery device incorporating thepresent invention that can be utilized in conjunction with a rapidexchange technique.

FIG. 9 a is an enlarged side-elevational view of the rapid exchangedembodiment of the mechanical dilatation and medicament delivery devicedemonstrating the guidewire entry ports in the inner and outer elongatedtubular members.

FIG. 10 is a side-elevational view of the distal extremity of the deviceshown in FIGS. 1-9 showing the distal extremity with the expansionmember in an expanded condition.

FIG. 11 is a cross sectional view of the flexible elongated elementsdemonstrating the passive or electrically active dispensing of theliposome or micelle-encapsulated therapeutic agent or medicament intothe vessel wall.

FIG. 12 is a cross sectional view demonstrating the dispensing of aliposome or micelle-encapsulated therapeutic agent or medicament frombands affixed to the inner tubular member located within the expandablemesh.

FIG. 13 is a cross sectional view of the one flexible elongate elementsof the expandable mesh demonstrating the passive or electrically activedispensing of a liposome or micelle-encapsulated therapeutic agent ormedicament from the elongate element.

FIG. 14 is a cross sectional view of one of the flexible elongateelements of the expandable mesh demonstrating the dispensing of theliposome or micelle-encapsulated therapeutic agent or medicamentincorporated within a substrate coating over the elongate element.

FIG. 15 is a cross sectional view of one of the flexible elongateelements of the expandable mesh demonstrating the dispensing of aliposome or micelle-encapsulated therapeutic agent or medicament withthe aid of electrical current.

FIG. 16 is a cross sectional side view of the flexible elongatedelements demonstrating the passive or electrically active dispensing ofthe liposome or micelle-encapsulated therapeutic agent or medicamentinto the vessel wall.

FIG. 17 is a cross section side view of a typical liposome or micelleencapsulating a generic medicament.

DETAILED DESCRIPTION OF THE DRAWINGS

In general, the present invention relates generally to devices that areused to dilate and dispense a medicament or therapeutic agent to anobstruction within a stenotic segment of a vessel. The device iscomprised of an cylindrical expansion member to be disposed in anobstruction in a vessel carrying flowing blood. The cylindricalexpansion member has first and second ends and an intermediate portionbetween the first and second ends. The cylindrical expansion member alsohas a flow passage extending therethrough with a diameter and alongitudinal central axis. The diameter of the flow passage is avariable with movement of the first and second ends relative to eachother along the longitudinal central axis from a diametricallycontracted position to a diametrically expanded condition. Thecylindrical expansion member is comprised of a plurality of flexibleelongate elements each of which extends helically about the longitudinalextending central axis. The flexible elongate elements are coated withone or more liposome or micelle-encapsulated medicaments, therapeuticagents, drugs, pharmaceuticals, plasmids, genes or other agents. For thepurposes of this application, the terms used, liposome ormicelle-encapsulated medicaments and therapeutic agents, will be used toencompass all the particular agents described herein. It is alsocontemplated that the liposome or micelle-encapsulated medicament ortherapeutic agent may be incorporated with a non-medicament substratethat has been previously or simultaneously coated on the flexibleelongate elements. Furthermore, an electrical means can be incorporatedinto the catheter system to cause 1) electrical bonding of thetherapeutic agent to the mesh and/or 2) active migration/dispersion ofthe agent into the vessel/tissues. In addition, the present inventioncan include coating one or more of the bands secured to the centralcatheter element within the expansion mesh with one or more therapeuticagents.

The plurality of the flexible elongate elements of the expansion meshhave a first common direction of rotation are axially displaced relativeto each other and cross a further plurality of the flexible elongateelements also axially displaced relative to each other but having asecond common direction opposite to that of the first direction ofrotation to form a braided cylindrical expansion member. The crossing ofthe flexible elongate elements occurs in an area of contact between theflexible elongate elements.

First and second means is provided respectively engaging the first andsecond ends of said cylindrical expansion member for retaining saidfirst and second ends in contracted positions. Means is provided forcausing relative axial movement of the first and second ends towardseach other to cause the intermediate cylindrical portion of theexpansion member to contract longitudinally and to expand diametricallyby causing the flexible elongate elements in the intermediate portion ofthe cylindrical member to move closer to each other expanding thediametric dimensions of the cylindrical expansion member therebyallowing it to contact the vessel wall and enable it to dilate anobstruction within the vessel. Flexible elongate elements at the firstand second ends of the cylindrical expansion member remain contractedaround and within first and second means and are thereby prevented frommoving closer which maintains spacing between the flexible elongatemembers so that blood in the vessel can continue to flow through thefirst and second ends and through the flow passage in the cylindricalexpansion member while the cylindrical expansion member is in engagementwith vessel wall and dilating an obstruction within the vessel.

More in particular as shown in FIGS. 1-7 of the drawings, the mechanicaldilatation and medicament delivery device 11 shown therein consists of afirst or outer flexible elongate tubular member 12 having proximal anddistal extremities 13 and 14 with the flow passage 16 extending from theproximal extremity 13 to the distal extremity 14. FIGS. 2, 3, 4, 5, and6 are provided to represent both the non-electrical conduction means andthe electrical conduction means embodiment that includes an electricalconduction means extending from the proximal connector and engaged tothe distal expansion member 31. A second or inner flexible tubularmember 21 is coaxially and slidably disposed within the flow passage 16of the first or outer flexible elongate tubular member 12 and isprovided with proximal and distal extremities 22 and 23 with a flowpassage 24 extending from the proximal extremity 22 to the distalextremity 23. If the flexible elongate elements of the dilating memberare made of a metallic material such as stainless steel, elgiloy orother conductive material, an electrical lead can be connected to themesh to make it part of the circuit. The electrical lead can either runalong or within one of the lumens of the catheter or can be in the formof a braid that is made of a conductive material and have generallyfunctions to provide reinforcement to the catheter shaft. A secondelectrode could be placed on the distal tip of the catheter via a smallband with its electrical lead running down one of the lumens to theproximal end of the catheter. Alternatively, the electircal lead couldbe engaged to the patient's skin or could be the guidewire over whichthe catheter is routinely advanced.

The flexible elongate elements of the catheter could be coated with apolymeric material or similar substrate onto which the liposome ormicelle-encapsulated medicament or theraputic agent could adsorb.Synthetic polymers or natural polymers can be used, such as amino acidpolymers or polysaccharides. The polymer is selected depending on thetherapeutic agent required, the polymer's compatibility with a patientand the ultimate pharmacologic effect desired. These polymers couldinclude hydrophilic polymers used for their absorptive properties ofaqueous solutions. The flexible elongate elements, either coated oruncoated, could then be submerged in a solution of a liposome ormicelle-encapsulated therapeutic agents or medicaments with a specificcharge and an electrical charge could be applied to render the flexibleelongate members opposite in charge to that of the liposome ormicelle-encapsulated therapeutic agent or medicament. This would createa significant bonding of the liposome or micelle-encapsulated agent ormedicament to the flexible elongate elements. Typically, the flexibleelongate elements of the mesh will be charged with the attached liposomeor micelle-encapsulated therapeutic agent or medicament just prior toadvancing the catheter through the patient's vasculature to the site ofdilatation and therapy without significant loss of the drug in thebloodstream. Once the site of obstruction or treatment is reached, thecharge on the mesh could be reversed using the same electrodes thusdriving the liposome or micelle-encapsulated therapeutic agent ormedicament into the target tissue. In this case, the electrode placed onthe skin of the patient would be used to cause active diffusion oriontophoresis of the therapeutic agent or medicament into the targettissues. As shown in FIGS. 8 a-8 f, the present invention can employflow of electrical current in the from of various waveforms to performthe iontophoresis and/or electroporation procedures. Possible waveformscontemplated for the present invention include square waves, rectangularwaves, saw-toothed waves, sinusoidal waves that do not reverse polarity,rectified sinusoidal waves, and other waveform shapes which may reversepolarity but provide a net flow of current in the desired direction.

Electrical current could also be coordinated with the patient'selctrocardiogram such that electrical current is provided to the meshonly during certain phases of cardiac depolarization. This “gating” ofthe electrical current would avoid the potential danger of dischargingelectrical current to the heart during vunerable phases ofdepolarization which may lead to cardiac arrhythmias.

Iontophoretically enhanced delivery requires that the therapeutic agentcarry a net charge under physiological conditions whereaselectroporation alone would be used for delivering treatment agents thatare not sufficiently ionized to iontophorese well into tissues.Electroporation may also be the preferred strategy for enhancinglocalized cellular targeting of a systemically administered therapeuticagent.

As used herein, the term “iontophoresis” means the migration ofionizable molecules through a medium driven by an applied low-levelelectrical potential. This electrically mediated movement of moleculesinto tissues is superimposed upon concentration gradient dependentdiffusion processes. If the medium or tissue through which the moleculestravel also carries a charge, some electro-osmotic flow occurs. However,generally, the rate of migration of molecules with a net negative chargetowards the positive electrode and vice versa is determined by the netcharge on the moving molecules and the applied electrical potential. Thedriving force may also be considered as electrostatic repulsion.Iontophoresis usually requires relatively low constant DC current in therange of from about 2-10 mA. In a well established application ofiontophoresis, that of enhancing drug delivery through the skin(transdermal iontophoresis), one electrode is positioned over thetreatment area and the second electrode is located at a remote site,usually somewhere else on the skin. With the present invention thereturn electrode may be similarly positioned on the skin. Alternativelythe tip of the guide wire emerging from the distal end of the supportcatheter may serve as the return electrode.

As used herein, the term “electroporation” means the temporary creationof holes or aqueous pores in the surface of a cell membrane by anapplied electrical potential and through which therapeutic agents maypass into the cell. Electroporation is now widely used in biology,particularly for transfection studies, where plasmids, DNA fragments andother genetic material are introduced into living cells. Duringelectroporation pulsing, molecules that are not normally membranepermeant are able to pass from the extracellular environment into thecells during the period of induced reversible membrane permeabilization.The permeabilized state is caused by the generation of an electricalfield in the cell suspension or tissue of sufficient field strength toperturb the cell surface membrane's proteolipid structure. Thisperturbation (sometimes referred to as dielectric breakdown) is believedto be due to both a constituent charge separation and the effect ofviscoelastic compression forces within the membrane and it'ssub-adjacent cytoskeletal structures. The result is a localized membranethinning. At a critical external field strength, pores or small domainsof increased permeability are formed in the membrane proteolipidbi-layer.

A guide wire 26 of a conventional type is adapted to be introducedthrough the flow passage 24 in the inner flexible elongate tubularmember for use in guiding the mechanical dilatation and medicamentdelivery device 11 as a over-the-wire design as hereinafter described.The guide wire 26 can be of a suitable size as for example 0.010″-0.035″and can have a suitable length ranging from 150 to 300 centimeters. Forexample, the first or outer flexible elongate tubular member 12 can havean outside diameter of 0.6-3 millimeters with a wall thickness of 0.12millimeters to provide a flow passage of 0.75 millimeters in diameter.Similarly, the second or inner flexible elongate tubular member 21 canhave a suitable outside diameter as for example 0.6 millimeters with awall thickness of 0.12 millimeters and a flow passage 24 of 0.45millimeters in diameter. The flexible elongate tubular members 12 and 21can be formed of a suitable plastic as for example a polyimide,polyethylene, Nylon or polybutylterphalate (PBT).

In accordance with the present invention an essentially cylindricallyshaped expansion member 31 is provided which has a first or proximal end32 and a second or distal end 33 with a central or inner flow passage 34extending from the proximal end 32 to the distal end 33 along alongitudinally extending central axis and has a diameter which is avariable as hereinafter described. The cylindrically shaped expansionmember 31 is comprised of a plurality of flexible elongate elements orfilaments 36 each of which extends helically about the longitudinallyextending central axis. The flexible elongate elements 36 are formed ofsuitable materials which can be utilized in the human blood as forexample stainless steel, Nitinol, Aermet™, Elgiloy™ or certain otherplastic fibers. The flexible elongate elements 36 can have a suitablediameter as for example 0.001 to 0.010 inches or can be configured as around, elliptical, flat or triangular wire ribbon. A plurality of theflexible elongate elements 36 have a first common direction of rotationabout the central axis as shown in FIGS. 1 and 7 are axially displacedrelative to each other and cross a further plurality of the flexibleelongate elements 36 also axially displaced relative to each other buthaving a second common direction of rotation opposite to that of thefirst direction of rotation to form a double helix or braided ormesh-like cylindrical expansion member with the crossing of flexibleelongate elements 36 occurring in the area of contact between theflexible elongate elements to form openings or interstices 37therebetween. Thus the flexible elongate elements 36 form an expansionmember 31 which provides a central or inner flow passage 34 which isvariable in diameter upon movement of the first and second ends of theexpansion member 31 relative to each other along the longitudinallyextending central axis.

Means is provided for constraining the first and second or proximal anddistal ends 32 and 33 of the expansion member 31 and consists of a firstor proximal collar 41 and a second or distal collar 42. The first andsecond collars 41 and 42 are formed of a suitable material such as apolyimide. The first or proximal collar 41 has a suitable length as forexample 1.0 to 5.0 millimeters and is sized so that it can fit over thefirst or proximal end 32 of the expansion member 31 when it is in acontracted position and over the distal extremity 14 of the first orouter flexible elongate member 12. In order to ensure that elongateelements or filaments 36 of the first or proximal extremity 32 arefirmly secured to the distal extremity 14 of the first or outer flexibleelongate member 12, an adhesive can be provided bonding the first orproximal end 32 to the collar 41 and to the distal extremity 14 of thefirst or outer flexible elongate tubular member 12. The second or distalcollar 42 can be of a suitable size and typically may be slightlysmaller in diameter because it need merely secure the elongate elementor filaments 36 of the distal end 33 of the expansion member 31 to thedistal extremity 23 of the second or inner flexible elongate tubularmember 21. An adhesive (not shown) is provided to firmly secure thesecond or distal end 33 of the expansion member 31 between the second ordistal collar 42 and the distal extremity of the inner flexible elongatetubular member 21. In this manner it can be seen that the cylindricalexpansion member 31 has its proximal end curved conically inward towardand secured to the distal extremity of the outer flexible elongatetubular member 12 and the second or distal end 33 of the expansionmember 31 also curves conically inward toward and is secured to thedistal extremity of the second or inner flexible elongate tubular member21.

Typically the distance between the first and second collars 41 and 42can range from between 5 to 150 millimeters. Typically the distal end 23of the second or inner flexible elongate tubular member 21 extendsapproximately 5-170 millimeters beyond the distal extremity 14 of thefirst or outer flexible elongate tubular member 12.

It can be seen that by moving the first or outer flexible elongatetubular member 12 and the second inner flexible elongate tubular member21 axially with respect to each other, the first and second ends of theexpansion member 31 are moved towards each other causing the elongateelements or filaments 36 of an intermediate portion of the cylindricalexpansion member between the first and second ends to move closer toeach other to cause these flexible elongate elements to move intoapposition with each other and to expand in a first radial direction theintermediate portion of the cylindrical expansion member 31 (FIG. 7) andto cause the diameter of the central flow passage 34 to increase. Theportions of the expansion member 31 immediately adjacent the first andsecond collars 41 and 42 remain restrained by the collars 41 and 42causing the flexible elongate elements 36 immediately adjacent to thecollars 41 and 42 to curve conically toward and remain crossed andunable to come into close apposition and thereby provide openings orinterstices 37 therebetween, which remain relatively constant in shapeand size so that blood can flow from the first and second ends 32 and 33through the central or inner flow passage 34 as hereinafter described.

The essentially cylindrical shape of the expansion member when expandedin a radial directon provides an enlarged surface of contact between theexpansion member and the vessel wall or obstruction. This enlargedsurface of contact enables the cylindrical expansion member to deliveran amount of medicament or therapeutic agent which is present on thesurface of the flexible elongate elements that comprise the expansionmember. This delivery of medicament or therpeutic agent may be by thevarious well known means previously described such as passive orelectrically active diffusion, pressure, iontophoresis orelectroporesis.

One example of the means provided in the mechanical dilatation andmedicament delivery device 11 for causing relative movement between thefirst or outer flexible elongate tubular member 12 and the second orinner flexible elongate tubular member 21 and consists of a linearmovement mechanism 46. The linear movement mechanism 46 includes aY-adapter 49 that is provided with a central arm 51 having a lumen 52through which the second or inner flexible elongate tubular member 21extends. The lumen or flow passage 52 is in communication with the lumen16 of outer flexible elongate tubular member 12 and with a flow passage53 in a side arm 54 which is adapted to receive a syringe (not shown) sothat saline, radiocontrast liquid or a medicament/therapeutic agent canbe introduced through the side arm 54 and into the flow passage 52 inthe Y-adapter 49 and thence into lumen 16 of outer member 12. The distalend of screw mechanism 46 is provided with a fitting 56 with inner lumen57 into which the proximal end 13 of flexible elongate tubular member 12is seated and held in place by an adhesive 58 at the distal end offitting 56. Lumen 57 is thereby in communication with flow passage 52 ofcentral arm 51 and with flow passage 53 of side arm 54. An O-ring 59that is adapted to form a fluid-tight seal with respect to the second orinner flexible tubular member 21 is disposed in the lumen 52 of thecentral arm 51. An interiorly threaded knurled knob 66 is threaded ontoan exteriorly threaded member 67 which is secured to and surrounds theproximal extremity 22 of inner flexible elongate tubular member 21. Theknob 66 is provided with an inwardly extending flange 68 which seats inan annular recess 69 in the central arm 51. Thus, rotation of the knob66 causes advancement or retraction of threaded member 67 and the secondor inner flexible elongate tubular member 21 with respect to the fitting56. Indicia 68 in the form of longitudinally spaced-apart rings 70 areprovided on the member 67 and serve to indicate the distance that thesecond or inner flexible elongate tubular member 21 has been advancedand retracted with respect to the first or outer flexible elongatemember 12.

A Luer-type fitting 71 is mounted on the proximal extremity 22 of theinner elongate flexible tubular member 21 and is adapted to be engagedby a finger of the hand. The guide wire 26 extends through the fitting71 and into the lumen 24 of inner elongate flexible tubular member 21.

It should be appreciated that even though one particular linear movementmechanism 46 has been provided for advancing and retracting the flexibleelongate members 12 and 21 with respect to each other, other mechanismsalso can be utilized if desired to provide such relative movement. Otherpossible designs that could be employed are scissors-jack, rachet-typeor straight slide mechanisms.

Another embodiment of a dilatation and medicament delivery deviceincorporating the present invention is shown in FIGS. 9 and 9 a. Asshown therein, the rapid exchange designed mechanical dilatation andmedicament delivery device 101 is constructed in a manner similar to themechanical dilatation and medicament delivery device 11 with theexception that it is provided with rapid exchange capabilities. This isaccomplished by providing an outer flexible elongate tubular member 102having a lumen 103 therein and an inner flexible elongate tubular member106 having a lumen 107 which have the expansion member 31 securedthereto by the proximal and distal collars 41 and 42. The outer flexibleelongate tubular member 102 is provided with a port or opening 111 intothe corresponding lumen 103 and which is 13-60 centimeters from thedistal extremity 32 of the expansion member 31. A corresponding port oropening 112 into corresponding lumen 107 is provided within the innerflexible elongate tubular member 106. These ports 111 and 112 arepositioned so that when the expansion member 31 is in its expandedposition with the distal extremities of the members 102 and 106 being inclosest proximity to each other, the openings 111 and 112 are inregistration with each other. In this position, the mechanicaldilatation and medicament delivery device 101 can be loaded onto theguide wire 16 by advancing the most proximal extremity of guide wire 26first into lumen 107 of the distal extremity of the inner flexibleelongate member 106 and then back through port or opening 112 and port111 which are in registration and out of the flexible elongate tubularmember 102. The expansion member 31 is next contracted from itsdiametrically expanded condition to a contracted condition by moving thedistal extremities of outer and inner flexible elongate tubular members102 and 106 further apart by operation of screw mechanism 46. Thisprocedure is performed while maintaining a stable position of theexternal position of guide wire 26 in a constant position in relation toport 111. As the distal extremity of flexible tubular member 106 ismoved further from the distal extremity of flexible elongate tubularmember 102, port 112 will move out of registration with port 111 whilemaintaining guide wire 26 within lumen 107 and advancing the distalextremity of the flexible elongate tubular member 106 along the guidewire 26. In this diametrically contracted state of the expansion member31, the mechanical dilatation and medicament delivery device 101 may beadvanced along guide wire 26 through the region of stenosis in the bloodvessel and enlargement of expansion member 31 may occur using screwmechanism 46 in the manner previously described. Once dilatation andmedicament delivery has been completed, expansion member 31 can bediametrically contracted and the mechanical dilatation and medicamentdelivery device 101 may be removed from the blood vessel and the guidingcatheter by maintaining a stable position of guide wire 26 in relationto the blood vessel and retracting device 101 along guide wire 26 untilthe distal extremity of inner flexible member 106 exits the patient'sbody. The mechanical dilatation and medicament delivery device 101 maynow be rapidly exchanged with another mechanical device 101 as forexample, one having an expansion member 31 which can be increased to alarger diameter over a standard 175 to 185 centimeter length guide wire26.

The expansion member 31 is comprised of 16-64 individual elements formedof 0.001 to 0.005 inch diameter wire of a suitable metal such asstainless steel helically wound around a longitudinal central axis. Thehelices are wound in opposite directions. Stretching or elongation ofthe cylindrical expansion member 31 results in a reduction in diameterof the expansion member 31. Mechanical fixation of the proximal anddistal extremities 22 and 23 of the expansion member 31 holds theseextremities in reduced diameter configurations. The positions of theelements 21 in these extremities cannot change in relation to eachother. Therefore, the crossing angles of the elements 36 remainconstant. Shortening of the cylindrical expansion member 31 with theends fixed results in the formation of a cylindrical center section ofgreat rigidity with the elements 36 in close apposition to each other.The tapered proximal and distal extremities of the expansion member 31causes the stresses on the individual elements 36 to be balanced. Sincethe proximal and distal extremities 22 and 23 are held in constanttapered positions, the interstices between the elements are maintainedallowing blood to flow into and out of the cylindrical center sectionwhen the expansion member 31 is shortened as shown in FIG. 10.Shortening of the expansion member 31 results in a significant increasein the metal density per unit length in the center portion of theexpansion member 31 while the metal density at the ends is relativelyconstant. This increase in metal density in the center section resultsin significant radial force generation as the elements 36 are compressedin a longitudinal direction.

As seen in FIG. 11 the flexible elongated elements 36 are coated with atherapeutic agent or medicament 40 resulting in a coated flexibleelongated element 35 that is designed to either passively orelectrically cause the therapeutic agent or medicament 40 to dispense ormigrate into the vessel wall 17. FIG. 13 demonstrates in a crosssectional view a more detailed view of one of the coated flexibleelongate elements 35 of the expandable mesh 31 designed to eitherpassively or electrically dispense the therapeutic agent or medicament40 from the elongate element 35. FIG. 12 shows a cross sectional viewdemonstrating the dispensing of a therapeutic agent or medicament frombands 62 affixed to the inner tubular member located within theexpandable mesh 31.

FIG. 14 is another cross sectional view of one of the coated flexibleelongate elements 35 of the expandable mesh 31 demonstrating thedispensing of the therapeutic agent or medicament 40 that isincorporated within a substrate 43 over the elongate element. Thesubstrate 43 can function to better adhere the medicament 40 to thesurface of the flexible elongate element 36, time the release of themedicament into the vessel wall 17, be an agent for transferring themedicament 40 across the cell membrane boundaries either by passive orpressure mediated transfer or actively by iontophoresis orelectroporation, or any combination of the services. FIG. 15 is anothercross sectional view of one of the coated flexible elongate elements 35of the expandable mesh 31 demonstrating the dispensing of a therapeuticagent or medicament 40 with the aid of electrical current applied to theflexible elongate elements.

FIG. 16 is a cross sectional side view of the flexible elongatedelements 36 demonstrating the passive or electrically active dispensingof the therapeutic agent or medicament 40 into the vessel wall 17.

To perform as a liposome or micelle-encapsulated therapeutic agent ormedicament source 40 for the present invention, the coated flexibleelongate elements 35 themselves can be coated as described in moredetail below.

A liposome or micelle-encapsulated therapeutic agent or medicament 40can be coated on (or incorporated into a polymer or other substrate 43and coated on the expansion mesh 31 and/or specific bands 62 mounted onthe catheter located within the expansion mesh. One particulartherapeutic agent or medicament 40 a can be coated upon any one of thecomponents described above, for example the expansion mesh and anothertherapeutic agent or medicament 40 b can be coated upon anothercomponent, for example, the marker bands. Alternately, a therapeuticagent delivery lumen that has a distal port located inside the expansionmember can be used to selectively release and deliver a particulartherapeutic agent or medicament.

The liposome or micelle-encapsulated therapeutic agent 40 can be ananticoagulant, such as D-Phe-Pro-Arg chloromethyl ketone, an RGDpeptide-containing compound, heparin, an antithrombin compound, aplatelet receptor antagonist, an anti-thrombin antibody, ananti-platelet receptor antibody, aspirin, a prostaglandin inhibitor, aplatelet inhibitor or a tick anti-platelet peptide.

The liposome or micelle-encapsulated therapeutic agent 40 can be apromoter of vascular cell growth, such as a growth factor stimulator, agrowth factor receptor agonist, a transcriptional activator, and atranslational promoter. Alternatively, the therapeutic agent 40 can bean inhibitor of vascular cell growth, such as a growth factor inhibitor,a growth factor receptor antagonist, a transcriptional repressor, atranslational repressor, an antisense DNA, an antisense RNA, areplication inhibitor, an inhibitory antibody, an antibody directedagainst growth factors, a bifunctional molecule consisting of a growthfactor and a cytotoxin, or a bifunctional molecule consisting of anantibody and a cytotoxin.

The liposome or micelle-encapsulated therapeutic agent 40 can be acholesterol-lowering agent, a vasodilating agent, or other agents thatinterfere with endogenous vasoactive mechanisms. Additionally, thetherapeutic agent 40 can be a smooth muscle inhibitor, such as: an agentthat modulates intracellular calcium binding proteins; a receptorblocker for contractile agonists; an inhibitor of the sodium/hydrogenantiporter; a protease inhibitor; a nitrovasodilator; aphosphodiesterase inhibitor; a phenothiazine; a growth factor receptoragonist; an anti-mitotic agent; an immunosuppressive agent; or a proteinkinase inhibitor.

Alternatively, the liposome or micelle-encapsulated therapeutic agent 40may be disposed on or within a substrate or polymer 43, which can bebiodegradable and adapted for slow release of the liposome ormicelle-encapsulated therapeutic agent 40. A substrate or polymer 43laden with one or more therapeutic agents 40 can be positioned on thebands, or coated on the flexible elongate elements 36.

A biodegradable substrate or polymer 43 such as polylactide,polyanhydride, polyorthoester or polyglycolide, for example can be used.In addition to synthetic polymers, natural polymers can be used, such asamino acid polymers or polysaccharides. The polymer 50 is selecteddepending on the therapeutic agent required, the polymer's 43compatibility with a patient and the ultimate pharmacologic effectdesired. For example, if the effect need only last a short period, athin polymer 43 can be used with a limited amount of therapeutic agentcapable of diffusing from the polymer 50 into the arterial wall or lumenof the vesicle. Alternatively, only the layer closest to the body fluidwould contain the liposome or micelle-encapsulated therapeutic agent 40.Another alternative would be to use a polymer 43 which is biodegradableover a long period of time. Naturally, the opposite characteristicswould be selected for a desired prolonged release.

Generally, the substrate or polymer 43 has a liposome ormicelle-encapsulated therapeutic agent 40 release rate of between about0.001 μg/cm²-min and about 100 μg/cm²-min, especially between about 0.01μg/cm²-min and 10 μg/cm²-min. In addition, the substrate or polymer 43generally has a thickness of between about 0.01 mm and 10 mm, especiallybetween about 0.1 mm and 1.0 mm. As can be appreciated, the device 10can be comprised of two or more different therapeutic agents 40 or twoor more different polymers 43 to obtain a desired effect and releaserate. In addition, the polymers 43 can have different solubilities ordiffusion characteristics to accomplish non-uniform therapeutic agent 40release.

The methodology for coating of a polymer and/or a therapeutic agent ormedicament onto the bands or flexible elongate elements of the expansionmember is well known to those skilled art or can be determined byreference to standard references. In addition, the characteristics ofthe particular substrate or polymer 43 for these purposes is well knownto the skilled artisan or can be determined by reference to standardreferences, e.g., Biodegradable Polymers as Therapeutic agent DeliverySystems, R. Langer and M. Chasin, Eds., Marcel Dekker Inc., New York,N.Y., USA (1990); Engleberg and Kohn, “Physico-mechanical properties ofdegradable polymers used in medical applications: a comparative study,”Bionuzterials 12:292-304 (1991); Controlled Release Delivery Systems, T.J. Roseman and S. D. Mansdorf, Eds., Marcel Dekker Inc., New York, N.Y.,USA (1983); and “Controlled Release Technology, PharmaceuticalApplications, ACS Symposium Series, Vol. 348, P. I. Lee and W. R. Good,Eds., American Chemical Society, Washington, D.C., USA (1987).

Operation and use of the mechanical dilatation and medicament deliverydevice 11 may now be briefly described as follows. Let it be assumedthat the patient which the medical procedure is to be performedutilizing the mechanical dilatation and medicament delivery device 11has one or more stenoses which at least partially occlude one or morearterial vessels supplying blood to the heart and that it is desired toenlarge the flow passages through these stenoses. Typically themechanical dilatation and medicament delivery device 11 would besupplied by the manufacturer with the cylindrical expansion member 31 inits most contracted position to provide the lowest possibleconfiguration in terms of diameter and so that the diameter approximatesthe diameter of the outer flexible elongate tubular member 12 andpreviously coated with a therapeutic agent or medicament 40.Alternatively, the mechanical dilatation and medicament delivery devicewill be supplied either uncoated or coated only with the bonding polymerpresent on the dilatation member and without any liposome ormicelle-encapsulated therapeutic agent or medicament 40 on the expansionmesh. In this example, a container having a solution of the liposome ormicelle-encapsulated therapeutic agent 40 can be separately suppliedwhereby sometime prior to inserting the mechanical dilatation andmedicament delivery device into the patient, the expansion mesh 31 isimmersed or dipped into the container in order to coat the flexibleelongate members 36. Appropriate time and/or temperatures will beallowed for the medicament solution to adsorb, dry and adhere to thepolymer coated expansion mesh, or alternately, a charge can be appliedto facilitate bonding of the medicament or therapeutic agent to thepolymer coated expansion member.

Preferably, the coated expansion member 35 should have a diameter thatis only slightly greater than the tubular member 12, as for example by1.0-2.3 millimeters. The first and second collars 41 and 42 also havebeen sized so they only have a diameter that is slightly greater thanthe outer diameter of the outer flexible elongate tubular member 12. Tobring the cylindrical expansion member 31 to its lowest configuration,the linear movement mechanism 46 has been adjusted so that there is amaximum spacing between the distal extremity 23 of the inner flexibleelongate tubular member 21 and the distal extremity 14 of the outerflexible elongate tubular member 12. In this position of the expansionmember 31, the flexible elongate elements 36 cross each other at nearlyright angles so that the interstices or openings 37 therebetween areelongated with respect to the longitudinal axis.

If applicable, the present invention has the flexible elongate elementsof the catheter coated with a liposome or micelle-encapsulatedmedicament or therapeutic agent that can be subjected to an electricalcurrent that renders the flexible elongate members to have a chargeopposite to that of the therapeutic agent or medicament. Applicableliposome or micelle-encapsulated therapeutic agents or medicaments willhave inherent charge potentials that when opposite charges are appliedto the expansion member, an electrical bond is established between thesurface of the expansion member and the liposome or micelle-encapsulatedtherapeutic agent or medicament. Electrical energy or current may beapplied from an electrical connector located on the proximal end of thecatheter, through the leads 45 and to the coated expansion member 35.This would create a significant bonding of the liposome ormicelle-encapsulated therapeutic agent or medicament 40 to the flexibleelongate elements 36. The continuously charged mesh with the attachedliposome or micelle-encapsulated therapeutic agent or medicament 40could then be advanced through the patient's vasculature to the site ofdilatation and therapy without significant loss of the medicament in thebloodstream.

The mechanical dilatation and medicament delivery device 11 is theninserted into a guiding catheter (not shown) typically used in such aprocedure and introduced into the femoral artery and having its distalextremity in engagement with the ostium of the selected coronary artery.

Thereafter, the guide wire 26 can be inserted independently of themechanical dilatation and medicament delivery device 11. If desired theguide wire 26 can be inserted along with the mechanical dilatation andmedicament delivery device 11 with its distal extremity extending beyondthe distal extremity of device 11. The guide wire 26 is then advanced ina conventional manner by the physician undertaking the procedure and isadvanced into the vessel containing a stenosis. The progress of thedistal extremity of the guide wire 26 is observed fluoroscopically andis advanced until its distal extremity extends distally of the stenosis.With the expansion member 31 in its diametrically contracted positionand the liposome or micelle-encapsulated medicament or therpeutic agentcoated thereon, the mechanical dilatation and medicament delivery device11 is advanced over the guide wire 26. The distal extremity 23 of thesecond or inner flexible elongate tubular member 21 is advanced throughthe stenosis over the guide wire 26 until it is distal to the stenosisand so that the distal extremity 14 of the first or outer flexibleelongate tubular member 12 is just proximal of the stenosis.

After the expansion member 31 is in a desired position in the stenosis,the expansion member 31 is expanded from its diametrically contractedposition to an expanded position by moving the distal extremities 14 and23 closer to each other by operation of the screw mechanism 46. This canbe accomplished by holding one distal extremity stationary and movingthe other distal extremity towards it or by moving both distalextremities closer to each other simultaneously. This movement of thedistal extremities 14 and 23 causes collars 41 and 42 to move closer toeach other and to cause the central flexible elongate elements 36forming the double helix mesh of the intermediate portion 31 a of theflexible cylindrical expansion member 31 to move relative to each otherto progressively decrease the vertical crossing angle of the doublehelically wound flexible elongate elements 36 from approximately 140° to170° in its extended state to 5° to 20° in its axially contracted stateand to progressively change the interstices or openings 37 fromdiamond-shaped openings with long axes parallel to the centrallongitudinal axis of the catheter in its extended state to substantiallysquare-shaped openings in its intermediately contracted state toelongate diamond-shaped interstices or openings with the longitudinalaxes extending in directions perpendicular to the central longitudinalaxis with the flexible elongate elements 36 coming into close appositionto each other while at the same time causing radial expansion of theexpansion member and to progressively increase the diameter of thecentral flow passage 34. The enlargement of expansion member 31 inaddition to being viewed fluoroscopically can also be ascertained by theindicia 68 carried by the threaded member 67.

The intermediate portion 31 a of the cylindrical expansion member 31when fully expanded is almost a solid tubular mass which has significantradial strength to fully expand a stenosis or alternatively a stent orprosthesis. In addition, because of spring-like properties of theenlarged expansion member being comprised of helically wound flexibleelongate elements 36, the expansion member 31 can conform to a curvewithin the blood vessel while still exerting significant radial force tothe stenosis or alternatively a stent or prosthesis and to make possiblecompression of the stenosis without tending to straighten the curve inthe vessel which typically occurs with standard straight angioplastyballoon systems. Since the expansion member or alternatively a stent orprosthesis is coated with a therapeutic agent or medicament one or moretherapeutic agents or medicaments can be delivered to the vessel duringthe time of device expansion while blood is permitted to flowunobstructed to the distal vessel (see FIGS. 11-16).

Additionally an electrical charge can be provided to the dilatationmember or mesh that is opposite in charge to that used to bind theliposome or micelle-encapsulated medicament to the mesh or expansionmember. This charge will then tend to drive the liposome ormicelle-encapsulated medicament or therapeutic agent into the tissuethrough iontophoretic means. The iontophoretic process is known tofacilitate or assist the transport of the liposome ormicelle-encapsulated medicament or therapeutic agent across theselectively permeable membranes and enhance tissue penetration. Sincethe present invention involves the use of electrical energy, there aremany possible waveforms contemplated for use. As depicted in FIGS. 8 a-8f, square waves 61, rectangular waves 63, saw toothed waves 64,sinusoidal waves that do not reverse polarity 65, rectified sinusoidalwaves, 72 and modified rectangular or other waves 73. The primarycharacteristic of the preferred waveforms is that they all provide a netflow of current to the coated expansion member 35. It must beappreciated by those skilled in the art, that the waveforms withfrequencies and duty cycles must be capable of delivering the desiredcurrent under varying impedances encountered by the expansion member 35and the surrounding vessel wall 17 and fluids.

After a predetermine time, the electrical current can be altered toachieve another purpose or terminated. Since blood flows continuouslythrough the dilatation and medicament delivery device 11 during thedilatation and medicament delivery procedure, there is minimal danger ofischemia occurring. This makes it possible to maintain dilatation andmedicament delivery 11 of the obstruction over extended periods of timewhen desired. One particularly advantage for the mechanical dilatationand medicament delivery device 11 is that it could be used with patientswhich have obstructions of a critical nature that cannot even toleraterelatively short periods of balloon dilatation without leading toischemia and creating permanent damage or shock to the patient. Anotheradvantage of the present invention is the increased contact area of thecylindrical expansion member with the vessel wall can lead to increasedadsorption of the medicament or therapeutic agent by the tissues.

After dilatation and medicament delivery of the lesion has been carriedout for an appropriate length of time, the expansion member 31 can bemoved from its expanded position to a contracted position by, forexample, operation of the screw mechanism 46 in a reverse direction tocause separation of the distal extremities 14 and 23 to thereby causeelongation of the expansion member 31 with a concurrent reduction indiameter.

After the expansion member 31 has been reduced to its contracted orminimum diameter, the mechanical dilatation and medicament deliverydevice 11 can be removed along with the guide wire 26 after which theguiding catheter (not shown) can be removed and the puncture siteleading to the femoral artery closed in a conventional manner.Alternately, the previously used mechanical dilatation and medicamentdelivery device 11 can be replaced and another mechanical dilatation andmedicament delivery device 11 which has fresh medicaments, differentmedicaments, or different expansion member 31 diameters for subsequenttreatment of the site.

Describe below are some examples of experiments conducted using thepresent invention.

EXAMPLE 1 Local Delivery of 7-Amino Actinomycin D

7-Amino Actinomycin D is a fluorescent (emits at 610 nm, [red]) analogof Actinomycin D, a potent inhibitor of cellular proliferation. It isvery lipophilic and poorly soluble in water. Liposome or micelles wereprepared by mixing 3.0 mg of phosphatidylcholine, 3.0 mg of cholesteroland 0.3 mg of phosphatidylserine in a test tube. Chloroform (200microliters) was added and the solution was evaporated to dryness in atest tube. 7-Amino Actinomycin D (500 mg) was dissolved in 8 mM CaCl₂for a final concentration of 0.5 mg/ml. The 7-Amino Actinomycin Dsolution was added to the lipid mixture in small aliquots with constantstirring. The hydrogel-coated metal mesh catheter was placed in the7-amino Actinomycin D/liposome or micelle mixture and then used for drugdelivery in the following manner: The hydrogel-coated metal meshcatheter was placed in the 7-Amino Actinomycin D/liposome or micellemixture and then removed. In some cases, the hydrogel-coated meshportion of the catheter was covered with a retractable sheath to preventloss of the compound during the transport of the catheter from thearterial access site to the target site. When the catheter waspositioned at the target site the sheath was retracted and the mesh wasexpanded against the arterial wall. Iontophoersis was performed byapplying an electrical current to the mesh. The circuit was completed bypacing a patch on the skin that was connected to the circuit and had anopposite charge than the mesh. In this example the iontophoresisparameters were 5 mA, and 8 V, applied for 10 minutes. The results alsoshow 7-Amino Actinomycin D throughout the vessel wall and in the outerlayer of the vessel. There is also evidence of localization of the7-Amino Actinomycin D in the nuclei of the cells.

EXAMPLE 2 Local Delivery of Paclitaxel

Paclitaxel is one of the most potent inhibitors of cellularproliferation in clinical use and has been shown to be efficacious in alarge number of cancers. Paclitaxel is very lipophilic and essentiallyinsoluble in water. Liposome or micelles were prepared by mixing 0.72 mgphosphatidylcholine and 0.8 mg of phosphatidylserine in a test tube with800 microliters of chloroform. The solution was evaporated to dryness.Paclitaxel labeled with a fluorescent probe (Oregon Green) was dissolvedin methanol to obtain a 20 1 mg/1 ml solution. Twenty-five microlitersof this solution was combined with 975 microliters of 8 mM CaCl₂. Thepaclitaxel solution was added to the dried lipid mixture in smallaliquots with constant stirring. The hydrogel-coated metal mesh catheterwas placed in the paclitaxel/liposome or micelle mixture and thenremoved. In some cases, the hydrogel-coated mesh portion of the catheteris covered with a retractable sheath to prevent loss of the compoundduring the transport of the catheter from the arterial access site tothe target site. When the catheter was positioned at the target site thesheath was retracted and the mesh was expanded against the arterialwall. Iontophoersis was performed by applying an electrical current tothe mesh. The circuit was completed by pacing a patch on the skin thatwas connected to the circuit and had an opposite charge than the mesh.In this example the iontophoresis parameters were 7 mA and 8 V, appliedfor 20 minutes. The results showed the paclitaxel throughout the vesselwall and in the outer layer of the vessel.

Although, the procedure hereinbefore described was for treatment of asingle stenosis, it should be appreciated that if desired during thesame time that the mechanical dilatation and medicament delivery device11 is within the guiding catheter, other vessels of the patient havingstenoses therein can be treated in a similar manner merely by retractingthe distal extremity of the mechanical dilatation and medicamentdelivery device 11 from the stenosis being treated, placing anotherprosthesis over the expansion member, and then advancing it into anotherstenosis in another vessel in a similar manner.

The advantages of using the present invention is the ability to delivera liposome or micelle-encapsulated therapeutic agent or medicament to avascular segment for prolonged periods while allowing continuousperfusion of blood into the distal to the treatment area.

From the foregoing, it can be seen that there has been provided amechanical dilatation and medicament delivery device which can be usedin a similar manner to a balloon catheter in dilating a vessel segmentor deploying a stent during an interventional procedure with theoutstanding advantage that blood can continue to flow to the distalblood vessel during the procedure while delivery of a liposome ormicelle encapsulated medicament or therapeutic agent is alsoaccomplished. This permits a longer vessel dilatation and medicamentdelivery without tissue ischemia. Furthermore, the dilatation andmedicament delivery device provides either passive or active delivery ofa medicament or therapeutic agent to the affected vessel walls via thecoated expansion member or via a stent or prostheis coated with such anagent. Furthermore, the mechanical dilatation and medicament deliverydevice also provides the advantages of known expanded non-compliantdiameter and therefore exact sizing.

1. A method for introducing liposomal encapsulated medicaments intocells of a patient, comprising the steps of: selecting a elongatedcatheter a substantially cylindrical shaped expansion member located ona distal end, said expansion member having a first end and a second end,said first end being a distance from said second end, an altering meansengagable to said first end and said second end of said expansion memberfor altering said first distance therebetween to move said expansionmember between a first configuration wherein said expansion member ischaracterized by a first diameter and a second configuration whereinsaid expansion member is characterized by a second diameter, said seconddiameter being greater than said first diameter; and a liposomeencapsulated medicament coated on at least a portion of said expansionmember; implanting said catheter into a selected blood vessel of apatient; expanding said expansion member wherein a portion of saidexpansion member contacts the vessel wall at a predetermine location;applying a predetermined electric signal to said expansion member toassist in transporting said liposome encapsulated medicaments acrosscell membranes.
 2. The method as recited in claim 1 which furthercomprises the step of positioning a guidewire in the body passageway,and wherein said advancing step is accomplished by threading saidexpansion member over said guidewire.
 3. The method as recited in claim1 which further comprises the step of allowing said expansion member tobe in said second expanded configuration for a predetermined period oftime after the dilatation step to further expose said obstruction to themedicament.
 4. The method as recited in claim 1, wherein said liposomeencapsulated medicament is an anticoagulant selected from the groupconsisting of D-Phe-Pro-Arg chloromethyl ketone, an RGDpeptide-containing compound, heparin, an antithrombin compound, aplatelet receptor antagonist, an anti-thrombin antibody, ananti-platelet receptor antibody, hirudin, hirulog,phe-pro-arg-chloromethyketone (Ppack), Factor VIIa, Factor Xa, aspirin,clopridogrel, ticlopidine, a prostaglandin inhibitor, a plateletinhibitor and a tick anti-platelet peptide, and combinations thereof. 5.The method as recited in claim 1, wherein said liposome encapsulatedmedicament is a promoter of vascular cell growth selected from the groupconsisting of a growth factor stimulator, a growth factor receptoragonist, a transcriptional activator, and a translational promoter, andcombinations thereof.
 6. The method as recited in claim 1, wherein saidliposome encapsulated medicament is an inhibitor of vascular cell growthselected from the group consisting of a growth factor inhibitor, agrowth factor receptor antagonist, a transcriptional repressor, atranslational repressor, an antisense DNA, an antisense RNA, syntheticDNA compounds, especially those with backbones that have been modifiedto inhibit enzymatic degradation (e.g. phosphorothioate compounds andmorpholino diamidate compounds), a replication inhibitor, an inhibitoryantibody, an antibody directed against growth factors, a bifunctionalmolecule consisting of a growth factor and a cytotoxin, and abifunctional molecule consisting of an antibody and a cytotoxin, doublestranded DNA, single stranded DNA, single stranded RNA and a doublestranded RNA and combinations thereof.
 7. The method as recited in claim1, wherein said liposome encapsulated medicament is selected from thegroup consisting of a cholesterol-lowering agent, a vasodilating agent,and agents which interfere with endogenous vasoactive mechanisms,estrogen, testosterone, steroid hormones, cortisol, dexamethasone,corticosteroids, thyroid hormones, thyroid hormones analogs, throidhormones antagonist, adrenocorticotrophic hormone, thyroid stimulatinghormone, thyroid releasing factor, thyroid releasing factor analogs,thyroid releasing factor antagonists and combinations thereof.
 8. Themethod as recited in claim 1, wherein said liposome encapsulatedmedicament is a smooth muscle inhibitor selected from the groupconsisting of an agent that modulates intracellular calcium bindingproteins, a receptor blocker for contractile agonists, an inhibitor ofthe sodium/hydrogen antiporter, a protease inhibitor, anitrovasodilator, a phosphodiesterase inhibitor, a phenothiazine, agrowth factor receptor agonist, an anti-mitotic agent, animmunosuppressive agent, and a protein kinase inhibitor, andcombinations thereof.
 9. The method as recited in claim 1, wherein saidliposome encapsulated medicament is a compound that inhibits cellularproliferation, Paclitaxel, Rapamycin, Actinomycin D, Methotrexate,Doxorubicin, cyclophosphamide, and 5-fluorouracil, 6-mercapatopurine,6-thioguanine, cytoxan, cytarabinoside, cis-platin, chlorambucil,busulfan, and any other drug that can inhibit cell proliferation, andcombinations thereof.
 10. The method as recited in claim 1 furthercomprising a plurality of said liposome encapsulated medicaments coatedon at least a portion of said expansion member.
 11. A method forintroducing micelle encapsulated medicaments into cells of a patient,comprising the steps of: selecting a elongated catheter a substantiallycylindrical shaped expansion member located on a distal end, saidexpansion member having a first end and a second end, said first endbeing a distance from said second end, an altering means engagable tosaid first end and said second end of said expansion member for alteringsaid first distance therebetween to move said expansion member between afirst configuration wherein said expansion member is characterized by afirst diameter and a second configuration wherein said expansion memberis characterized by a second diameter, said second diameter beinggreater than said first diameter; and a micelle encapsulated medicamentcoated on at least a portion of said expansion member; implanting saidcatheter into a selected blood vessel of a patient; expanding saidexpansion member wherein a portion of said expansion member contacts thevessel wall at a predetermine location; applying a predeterminedelectric signal to said expansion member to assist in transporting saidmicelle encapsulated medicaments across cell membranes.
 12. The methodas recited in claim 11 which further comprises the step of positioning aguidewire in the body passageway, and wherein said advancing step isaccomplished by threading said expansion member over said guidewire. 13.The method as recited in claim 11 which further comprises the step ofallowing said expansion member to be in said second expandedconfiguration for a predetermined period of time after the dilatationstep to further expose said obstruction to the medicament.
 14. Themethod as recited in claim 11, wherein said micelle encapsulatedmedicament is an anticoagulant selected from the group consisting ofD-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound,heparin, an antithrombin compound, a platelet receptor antagonist, ananti-thrombin antibody, an anti-platelet receptor antibody, hirudin,hirulog, phe-pro-arg-chloromethyketone (Ppack), Factor VIIa, Factor Xa,aspirin, clopridogrel, ticlopidine, a prostaglandin inhibitor, aplatelet inhibitor and a tick anti-platelet peptide, and combinationsthereof.
 15. The method as recited in claim 11, wherein said micelleencapsulated medicament is a promoter of vascular cell growth selectedfrom the group consisting of a growth factor stimulator, a growth factorreceptor agonist, a transcriptional activator, and a translationalpromoter, and combinations thereof.
 16. The method as recited in claim11, wherein said micelle encapsulated medicament is an inhibitor ofvascular cell growth selected from the group consisting of a growthfactor inhibitor, a growth factor receptor antagonist, a transcriptionalrepressor, a translational repressor, an antisense DNA, an antisenseRNA, synthetic DNA compounds, especially those with backbones that havebeen modified to inhibit enzymatic degradation (e.g. phosphorothioatecompounds and morpholino diamidate compounds), a replication inhibitor,an inhibitory antibody, an antibody directed against growth factors, abifunctional molecule consisting of a growth factor and a cytotoxin, anda bifunctional molecule consisting of an antibody and a cytotoxin,double stranded DNA, single stranded DNA, single stranded RNA and adouble stranded RNA and combinations thereof.
 17. The method as recitedin claim 11, wherein said micelle encapsulated medicament is selectedfrom the group consisting of a cholesterol-lowering agent, avasodilating agent, and agents which interfere with endogenousvasoactive mechanisms, estrogen, testosterone, steroid hormones,cortisol, dexamethasone, corticosteroids, thyroid hormones, thyroidhormones analogs, throid hormones antagonist, adrenocorticotrophichormone, thyroid stimulating hormone, thyroid releasing factor, thyroidreleasing factor analogs, thyroid releasing factor antagonists andcombinations thereof.
 18. The method as recited in claim 11, whereinsaid micelle encapsulated medicament is a smooth muscle inhibitorselected from the group consisting of an agent that modulatesintracellular calcium binding proteins, a receptor blocker forcontractile agonists, an inhibitor of the sodium/hydrogen antiporter, aprotease inhibitor, a nitrovasodilator, a phosphodiesterase inhibitor, aphenothiazine, a growth factor receptor agonist, an anti-mitotic agent,an immunosuppressive agent, and a protein kinase inhibitor, andcombinations thereof.
 19. The method as recited in claim 11, whereinsaid micelle encapsulated medicament is a compound that inhibitscellular proliferation, Paclitaxel, Rapamycin, Actinomycin D,Methotrexate, Doxorubicin, cyclophosphamide, and 5-fluorouracil,6-mercapatopurine, 6-thioguanine, cytoxan, cytarabinoside, cis-platin,chlorambucil, busulfan, and any other drug that can inhibit cellproliferation, and combinations thereof.
 20. The method as recited inclaim 11 further comprising a plurality of said micelle encapsulatedmedicaments coated on at least a portion of said expansion member.
 21. Amethod for dilating and delivering a medicament to an obstruction in abody passageway which comprises the steps of: advancing a mechanicaldilatation catheter to a predetermined site with a body passageway, saidcatheter having an expansion member coated with a medicament and aniontophoretic transport means, said expansion member being moveablebetween a first contracted configuration wherein said member is definedby a first dimension extending in a radial direction, and a secondexpanded configuration wherein said member is defined by a seconddimension extending in said radial direction; applying a force on saidexpansion member in an axial direction to move said expansion memberbetween said first contracted configuration to said second expandedconfiguration wherein said obstruction is dilated; supplying a flow ofelectrical current to said iontophoretic means to deliver said liposomeor micelle-encapsulated medicament into said obstruction or bodypassageway.
 22. The method as recited in claim 21 which furthercomprises the step of positioning a guidewire in the body passageway,and wherein said advancing step is accomplished by threading saidcatheter over said guidewire.
 23. The method as recited in claim 21which further comprises the step of allowing said expansion member to bein said second expanded configuration for a predetermined period of timeafter the dilatation step to further expose said obstruction to themedicament.
 24. The method as recited in claim 21 which furthercomprises the step of varying the electric current with time to providea waveform that controls the rate of iontophoretic transport of saidmedicament.
 25. The method as recited in claim 21, further comprising,prior to advancing the catheter, the step of applying electrical energyto said expansion member to cause said medicament or therapeutic agentto electrically bond to said expansion member.
 26. A method for dilatingand delivering a medicament to an obstruction in a body passageway whichcomprises the steps of: advancing a mechanical dilatation catheter to apredetermined site with a body passageway, said catheter having anexpansion member coated with a medicament and an iontophoretic transportmeans, said expansion member being moveable between a first contractedconfiguration wherein said member is defined by a first dimensionextending in a radial direction, and a second expanded configurationwherein said member is defined by a second dimension extending in saidradial direction; applying a force on said expansion member in an axialdirection to move said expansion member between said first contractedconfiguration to said second expanded configuration wherein saidobstruction is dilated; supplying a flow of electrical current to saidiontophoretic means to deliver said liposome or micelle-encapsulatedmedicament into said obstruction or body passageway.
 27. The method asrecited in claim 26 which further comprises the step of positioning aguidewire in the body passageway, and wherein said advancing step isaccomplished by threading said catheter over said guidewire.
 28. Themethod as recited in claim 26 which further comprises the step ofallowing said expansion member to be in said second expandedconfiguration for a predetermined period of time after the dilatationstep to further expose said obstruction to the medicament.
 29. Themethod as recited in claim 26 which further comprises the step ofvarying the electric current with time to provide a waveform thatcontrols the rate of iontophoretic transport of said medicament.
 30. Themethod as recited in claim 26, further comprising, prior to advancingthe catheter, the step of applying electrical energy to said expansionmember to cause said medicament or therapeutic agent to electricallybond to said expansion member.